In search of selective and potent Golgi alpha-mannosidase II inhibitors as potential anticancer agents: Synthesis of 3-substituted-swainsonine analogs and preparation of immobilized swainsonine analogs on solid support

The major goal of this thesis research is to design and synthesize analogs of swainsonine that may be more selective and potent inhibitors for Golgi α-mannosidase II, but devoid of inhibitory activities toward lysosomal α-mannosidase. Alpha-3-benzyloxymethyl substitutions on swainsonine were tolerated well by mannosidases, while the respective beta-substitution rendered the analogs inactive. The first synthesis of a pseudodisaccharide with swainsonine at the glycone portion was accomplished. Although the pseudodisaccharide mimics the Man(α-1,6)Man disaccharide portion of the natural substrate, it showed low biological activities toward mannosidases. Polyethylene glycol linked swainsonine analogs were designed to bind both the active site and the putative GlcNAc binding site of Golgi α-mannosidase II. However, they were only weak inhibitors of mannosidases. Also, C3- and C6-derivatized swainsonine analogs were synthesized and used to prepare affinity columns for the purification of α-mannosidases. The C3-α-swainsonine affinity analogs were found to be potent α-mannosidase inhibitors. None of the synthesized C3-substituted swainsonine analogs showed significant selectivity in favor of Golgi α-mannosidase II.